The class of peptide pressor hormone known as angiotensin is responsible for a vasopressor action that is implicated in the etiology of hypertension in man. Inappropriate activity of the renin-angiotensin systems appears to be a key element in essential hypertension, congestive heart failure and in some forms of renal disease. In addition to a direct action on arteries and arterioles, angiotensin II (AII), being one of the most potent endogenous vasoconstrictors known, exerts stimulation on the release of aldosterone from the adrenal cortex. Therefore, the renin-angiotensin system, by virtue of its participation in the control of renal sodium handling, plays an important role in cardiovascular hemeostasis.
Interruption of the renin-angiotensin system with converting enzyme inhibitors, such as captopril, has proved to be clinically useful in the treatment of hypertension and congestive heart failure (Abrams, W. B., et al., (1984), Federation Proc., 43, 1314). The most direct approach towards inhibition of the renin-angiotensin system would block the action of AII at the receptor. Compelling evidence suggests that AII also contributes to renal vasoconstriction and sodium retention that is characteristic of a number of disorders such as heart failure, cirrhosis and complications of pregnancy (Hollenberg, N. K., (1984), J. Cardiovas. Pharmacol., 6, S176). In addition, recent animal studies suggest that inhibition of the renin-angiotensin system may be beneficial in halting or slowing the progression of chronic renal failure (Anderson, S., et al., (1985), J. Clin. Invest., 76, 612). Also, a recent patent application (South African Patent Application No. 87/01,653) claims that AII antagonists are useful as agents for reducing and controlling elevated intraocular pressure, especially glaucoma, in mammals.
The compounds described herein inhibit, block and antagonize the action of the hormone AII, and are therefore useful in regulating and moderating angiotensin induced hypertension, congestive heart failure, renal failure and other disorders attributed to the actions of AII. When the AII receptor blocking compounds are administered to mammals, the elevated blood pressure due to AII is reduced and other manifestations based on AII intercession are minimized and controlled. These compounds are also expected to exhibit diuretic activity.
One of the drawbacks of current antihypertensive therapy is that cardiovascular morbidity and mortality is higher in treated hypertensive patients than in normotensive subjects of the same age, sex, and from the same population [Isles, et al., J. Hypertension, 4, 141 (1986) and Samuelsson, O., Acta Med. Scand, Suppl. 702, 1 (1985)]. A possible explanation for this result is that arterial pressure in treated hypertensive patients is significantly higher than in matched normotensive subjects. Thus, it would appear that a therapeutic goal for the treatment of hypertension would be to obtain normotensive blood pressure levels in treated hypertensive patients [Hansson, L., Br. J. Clin. Pharmacol., 23, 15S (1987)]. To achieve this goal, the instant invention involves the administration of an agiotensin II receptor blocking compound in combination with a second agent, such as a diuretic, a calcium channel blocker, a .beta.-adrenoceptor blocker, a renin inhibitor, or an angiotensin converting enzyme inhibitor.
According to the present invention there are provided pharmaceutical compositions comprising a pharmaceutically acceptable carrier in association with a diuretic and an angiotensin II blocking agent of formula (I)-(IX), hereinbelow.
Substituted imidazoles of the formula (I) are disclosed in U.S. application Ser. No. 07/746,262, filed Aug. 14, 1991: ##STR1## in which:
R.sup.1 is adamantyl, phenyl, biphenyl, or naphthyl, with each aryl group being unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I, C.sub.1 -C.sub.6 alkyl, nitro, A--CO.sub.2 R.sup.7, tetrazol-5-yl, C.sub.1 -C.sub.6 alkoxy, hydroxy, SC.sub.1 -C.sub.6 alkyl, SO.sub.2 NHR.sup.7, NHSO.sub.2 R.sup.7, SO.sub.3 H, CONR.sup.7 R.sup.7, CN, SO.sub.2 C.sub.1 -C.sub.6 alkyl, NHSO.sub.2 R.sup.7, PO(OR.sup.7).sub.2, NR.sup.7 R.sup.7, NR.sup.7 COH, NR.sup.7 COC.sub.1 -C.sub.6 alkyl, NR.sup.7 CON(R.sup.7).sub.2, NR.sup.7 COW, W, or SO.sub.2 W;
m is 0-4;
R.sup.2 is C.sub.2 -C.sub.10 alkyl, C.sub.3 -C.sub.10 alkenyl, C.sub.3 -C.sub.10 alkynyl, C.sub.3 -C.sub.6 cycloalkyl, or (CH.sub.2).sub.0-8 phenyl unsubstituted or substituted by one to three substituents selected from C.sub.1 -C.sub.6 alkyl, nitro, Cl, Br, F, I, hydroxy, C.sub.1 -C.sub.6 alkoxy, NR.sup.7 R.sup.7, CO.sub.2 R.sup.7, CN, CONR.sup.7 R.sup.7, W, tetrazol-5-yl, NR.sup.7 COC.sub.1 -C.sub.6 alkyl, NR.sup.7 COW, SC.sub.1 -C.sub.6 alkyl, SO.sub.2 W, or SO.sub.2 C.sub.1 -C.sub.6 alkyl;
X is a single bond, S, NR.sup.7, or O;
R.sup.3 is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl, COOR.sup.7, CONR.sup.7 R.sup.7, NO.sub.2, W, CN, NR.sup.7 R.sup.7, or phenyl;
R.sup.4 and R.sup.5 are independently hydrogen, C.sub.1 -C.sub.6 alkyl, thienyl-Y-, furyl-Y-, pyrazolyl-Y-, imidazolyl-Y-, pyrrolyl-Y-, triazolyl-Y-, oxazolyl-Y-, isoxazolyl-Y-, thiazolyl-Y-, pyridyl-Y-, or tetrazolyl-Y-, except that R.sup.4 and R.sup.5 are not both selected from hydrogen and C.sub.1 -C.sub.6 alkyl and each heterocyclic ring is unsubstituted or substituted by C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, Cl, Br, F, I, NR.sup.7 R.sup.7, CO.sub.2 R.sup.7, SO.sub.2 NHR.sup.7, SO.sub.3 H, or CONR.sup.7 R.sup.7, OH, NO.sub.2, W, SO.sub.2 W, SC.sub.1 -C.sub.6 alkyl, SO.sub.2 C.sub.1 -C.sub.6 alkyl, NR.sup.7 COH, NR.sup.7 COW, or NR.sup.7 COC.sub.1 -C.sub.6 alkyl;
Y is a single bond, O, S, or C.sub.1 -C.sub.6 alkyl which is straight or branched or optionally substituted by phenyl or benzyl, wherein each of the aryl groups is unsubstituted or substituted by halo, NO.sub.2, CF.sub.3, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, CN, or CO.sub.2 R.sup.7 ;
R.sup.6 is --Z--COOR.sup.8 or --Z--CONR.sup.7 R.sup.7 ;
Z is a single bond, vinyl, --CH.sub.2 --O--CH.sub.2 --, methylene optionally substituted by C.sub.1 -C.sub.6 alkyl, one or two benzyl groups, thienylmethyl, or furylmethyl, or --C(O)NHCHR.sup.9 --, wherein R.sup.9 is H, C.sub.1 -C.sub.6 alkyl, phenyl, benzyl, thienylmethyl, or furylmethyl;
W is C.sub.n F.sub.2n+1, C.sub.n F.sub.2n+1, wherein n is 1-3;
A is --(CH.sub.2).sub.m --, --CH.dbd.CH--, --O(CH.sub.2).sub.n --, or --S(CH.sub.2).sub.n --;
each R.sup.7 independently is hydrogen, C.sub.1 -C.sub.6 alkyl, or (CH.sub.2).sub.m phenyl, wherein m is 0-4; and PA1 (E)-3-[2-n-butyl-1-{4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl) methyl-2-propenoic acid, PA1 (E)-3-[2-n-butyl-1-{(4-carboxynaphth-1-yl)methyl}-1H-imidazol-5-yl]-2-(2-th ienyl)methyl-2-propenoic acid, PA1 (E)-3-[2-n-butyl-1-{2-chloro-4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2 -thienyl)methyl-2-propenoic acid, and PA1 (E)-3-[2-n-butyl-1-{4-carboxy-2,3-dichlorophenyl)methyl}-1H-imidazol-5-yl]- 2-(2-thienyl)methyl-2-propenoic acid; or a pharmaceutically acceptable salt thereof. PA1 (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(3,4-methyl enedioxyphenyl)methyl-2-propenoic acid, PA1 (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-n-butyl-2- propenoic acid, and PA1 (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-benzyl-2-p ropenoic acid; or a pharmaceutically acceptable salt thereof. PA1 (E)-1-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(1H-tetraz ol-5-yl)-3-(2-thienyl) -1-propene, (E)-1-[2-n-butyl-1-{(4-(1H-tetrazol-5-yl)phenyl)methyl}-1H-imidazol-5-yl]- 2-(1H-tetrazol-5-yl) -3-(2-thienyl)-1-propene, and PA1 (E)-1-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(1H-tetrazo l-5-yl)-3-(2-thienyl)-1-propene; or a pharmaceutically acceptable salt thereof. PA1 N-[{1-(4-carboxyphenyl)methyl]-2-n-butyl-1H-imidazol-5-yl}methyl]-.beta.-(2 -thienyl)alanine, PA1 N-[{1-(2-chlorophenyl)methyl]-2-n-butyl-1H-imidazol-5-yl}methyl]-.beta.-(2- thienyl)alanine, and PA1 N-[{1-[(2-chlorophenyl)methyl]-2-n-butyl-1H-imidazol-5-yl}methyl]phenylalan ine; PA1 5-bromo-2-n-butyl-1-(2-chlorophenyl)methyl-1H-benzimidazole-7-carboxylic acid, PA1 2-n-butyl-1-(2-chlorophenyl)methyl-1H-benzimidazole-7-carboxylic acid, and PA1 2-n-butyl-1-(4-carboxyphenyl)methyl-5-chloro-1H-benzimidazole-7-carboxylic acid;
R.sup.8 is hydrogen, C.sub.1 -C.sub.6 alkyl, or 2-di(C.sub.1 -C.sub.6 alkyl)amino-2-oxoethyl; or a pharmaceutically acceptable salt thereof.
Preferred compounds included within the scope of formula (I) are:
Particularly preferred are (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thieny l)methyl-2-propenoic acid and (E) -3-[2-n-butyl-1-{(4-carboxynaphth-1-yl)methyl}-1H-imidazol-5-yl]-2-(2-thie nyl)methyl-2-propenoic acid, or a pharmaceutically acceptable salt thereof.
The most preferred compound of this invention is (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl]-1H-imidazolyl-5-yl]-2-(2-thie nyl)methyl-2-propenoic acid methanesulfonate.
Compounds of formula (I) are prepared following the methods described in European Patent Publication Number EP 0 403 159, published on Dec. 19, 1990.
Substituted imidazoles of the formula (II) are disclosed U.S. application Ser. No. 07/747,024, filed Aug. 14, 1991: ##STR2## in which:
R.sup.1 is adamantyl, phenyl, biphenyl, or naphthyl, with each aryl group being unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I, C.sub.1 -C.sub.6 alkyl, nitro, A--CO.sub.2 R.sup.7, tetrazol-5-yl, C.sub.1 -C.sub.6 alkoxy, hydroxy, SC.sub.1 -C.sub.6 alkyl, SO.sub.2 NHR.sup.7, NHSO.sub.2 R.sup.7, SO.sub.3 H, CONR.sup.7 R.sup.7, CN, SO.sub.2 C.sub.1 -C.sub.6 alkyl, NHSO.sub.2 R.sup.7, PO(OR.sup.7).sub.2, NR.sup.7 R.sup.7, NR.sup.7 COH, NR.sup.7 COC.sub.1 -C.sub.6 alkyl, NR.sup.7 CON(R.sup.7).sub.2, NR.sup.7 COW, W, SO.sub.2 W;
m is 0-4;
R.sup.2 is C.sub.2 -C.sub.10 alkyl, C.sub.3 -C.sub.10 alkenyl, C.sub.3 -C.sub.10 alkynyl, C.sub.3 -C.sub.6 cycloalkyl, or (CH.sub.2).sub.0-8 phenyl unsubstituted or substituted by one to three substituents selected from C.sub.1 -C.sub.6 alkyl, nitro, Cl, Br, F, I, hydroxy, C.sub.1 -C.sub.6 alkoxy, NR.sup.7 R.sup.7, CO.sub.2 R.sup.7, CN, CONR.sup.7 R.sup.7, W, tetrazol-5-yl, NR.sup.7 COC.sub.1 -C.sub.6 alkyl, NR.sup.7 COW, SC.sub.1 -C.sub.6 alkyl, SO.sub.2 W, or SO.sub.2 C.sub.1 -C.sub.6 alkyl;
X is a single bond, S, NR.sup.7, or O;
R.sup.3 is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl, COOR.sup.7, CONR.sup.7 R.sup.7, NO.sub.2, W, CN, NR.sup.7 R.sup.7, or phenyl;
R.sup.4 and R.sup.5 are independently hydrogen, C.sub.1 -C.sub.6 alkyl, phenyl-Y-, naphthyl-Y-, or biphenyl-Y-, wherein the aryl groups are unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I, C.sub.1 -C.sub.6 alkoxy, hydroxy, CO.sub.2 R.sup.7, CN, NO.sub.2, tetrazol-5-yl, SO.sub.3 H, CF.sub.3, CONR.sup.7 R.sup.7, SO.sub.2 NHR.sup.7, C.sub.1 -C.sub.6 alkyl, or NR.sup.7 R.sup.7, or by methylenedioxy, phenoxy or phenyl, except that R.sup.4 and R.sup.5 are not both selected from hydrogen;
Y is a single bond, O, S, or C.sub.1 -C.sub.6 alkyl which is straight or branched or optionally substituted by phenyl or benzyl, wherein each of the aryl groups is unsubstituted or substituted by halo, NO.sub.2, CF.sub.3, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, CN, or CO.sub.2 R.sup.7 ;
R.sup.6 is --Z--COOR.sup.8 or --Z--CONR.sup.7 R.sup.7 ;
Z is a single bond, vinyl, --CH.sub.2 --O--CH.sub.2 --, methylene optionally substituted by C.sub.1 -C.sub.4 alkyl, one or two benzyl groups, thienylmethyl, or furylmethyl, or --C(O)NHCHR.sup.9 --, wherein R.sup.9 is H, C.sub.1 -C.sub.4 alkyl, phenyl, benzyl, thienylmethyl, or furylmethyl;
each R.sup.7 independently is hydrogen, C.sub.1 -C.sub.4 alkyl, or (CH.sub.2).sub.m phenyl, wherein m is 0-4; and
R.sup.8 is hydrogen, C.sub.1 -C.sub.6 alkyl, or 2-di(C.sub.1 -C.sub.4 alkyl)-amino-2-oxoethyl; or
R.sup.5 and R.sup.6 are both hydrogen, R.sup.4 is --Z--COOR.sup.8 and Z is other than a single bond; or a pharmaceutically acceptable salt thereof.
Compounds of formula (II) are prepared following the methods described in European Publication Number EP 0 403 158, published on Dec. 19, 1990.
Preferred compounds included within the scope of formula (II) are:
Substituted imidazoles of the formula (III) are disclosed in U.S. application Ser. No. 07/590,207, filed Sep. 28, 1990: ##STR3## in which:
R.sup.1 is adamantylmethyl, or phenyl, biphenyl, or naphthyl, with each aryl group being unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I, C.sub.1 -C.sub.6 alkyl, nitro, CO.sub.2 R.sup.7, C.sub.1 -C.sub.6 alkoxy, hydroxy, SC.sub.1 -C.sub.6 alkyl, SO.sub.2 C.sub.1 -C.sub.6 alkyl, tetrazol-5-yl, SO.sub.2 NHR.sup.7, NHSO.sub.2 R.sup.7, SO.sub.3 H, PO(OR.sup.7).sub.2, CONR.sup.7 R.sup.7, CN, NR.sup.7 R.sup.7, NR.sup.7 COH, NR.sup.7 COC.sub.1 -C.sub.6 alkyl, NR.sup.7 CON(R.sup.7).sub.2, NR.sup.7 COW, SO.sub.2 W, or W; R.sup.2 is C.sub.2 -C.sub.10 alkyl, C.sub.3 -C.sub.10 alkenyl, (CH.sub.2).sub.0-8 -C.sub.3 -C.sub.6 cycloalkyl, or (CH.sub.2).sub.0-8 phenyl unsubstituted or substituted by one to three substituents selected from C.sub.1 -C.sub.6 alkyl, nitro, Cl, Br, F, I, hydroxy, C.sub.1 -C.sub.6 alkoxy, NR.sup.7 R.sup.7, CO.sub.2 R.sup.7, CN, CONR.sup.7 R.sup.7, W, NR.sup.7 COH, NR.sup.7 COC.sub.1 -C.sub.6 alkyl, NR.sup.7 COW, SO.sub.2 W, SO.sub.2 C.sub.1 -C.sub.6 alkyl, or SC.sub.1 -C.sub.6 alkyl;
X is a single bond, S, or O;
m is 0-4;
R.sup.3 is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl, C.sub.1 -C.sub.6 alkyl, NR.sup.7 R.sup.7, CO.sub.2 R.sup.7, CONR.sup.7 R.sup.7, NO.sub.2, CN, phenyl, or W;
R.sup.4 and R.sup.5 are each independently hydrogen, C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.6 cycloalkyl, thienyl-Y-, furyl-Y-, pyrazolyl-Y-, imidazolyl-Y-, thiazolyl-Y-, pyridyl-Y-, tetrazolyl-Y-, pyrrolyl-Y-, triazolyl-Y-, oxazolyl-Y-, isoxazolyl-Y-, or phenyl-Y-, with each aryl or heteroaryl group being unsubstituted or substituted by C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, Cl, Br, F, I, NR.sup.7 R.sup.7, CO.sub.2 R.sup.7, SO.sub.2 NHR.sup.7, SO.sub.3 H, OH, NO.sub.2, CONR.sup.7 R.sup.7, W, SO.sub.2 C.sub.1 -C.sub.6 alkyl, SO.sub.2 W, SC.sub.1 -C.sub.6 alkyl; NR.sup.7 COH, NR.sup.7 COW, or NR.sup.7 COC.sub.1 -C.sub.6 alkyl;
Y is C.sub.1 -C.sub.6 alkyl which is straight or branched or a single bond;
R.sup.6 is Z-tetrazol-5-yl;
Z is a single bond, vinyl, or methylene unsubstituted or substituted by C.sub.1 -C.sub.4 alkyl, one or two benzyl groups, thienylmethyl, or furylmethyl;
W is C.sub.n F.sub.2n+1, wherein n is 1-4; and
each R.sup.7 independently is hydrogen or C.sub.1 -C.sub.6 alkyl;
or a pharmaceutically acceptable salt thereof.
Preferred compounds included within the scope of formula (III) are:
Compounds of formula (III) are prepared following the methods described in European Publication Number EP 0 425 211, published on May 2, 1991.
Substituted imidazoles of the formula (IV) are disclosed in U.S. application Ser. No. 07/590,206, filed Sep. 28, 1990: ##STR4## in which:
R is adamantylmethyl, or phenyl, biphenyl, or naphthyl, with each aryl group being unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I, C.sub.1 -C.sub.6 alkyl, nitro, CO.sub.2 R.sup.7, C.sub.1 -C.sub.6 alkoxy, hydroxy, SC.sub.1 -C.sub.6 alkyl, SO.sub.2 C.sub.1 -C.sub.6 alkyl, tetrazol-5-yl, SO.sub.2 NHR.sup.7, NHSO.sub.2 R.sup.7, SO.sub.3 H, PO(OR.sup.7).sub.2, CONR.sup.7 R.sup.7, CN, NR.sup.7 R.sup.7, NR.sup.7 COH, NR.sup.7 COC.sub.1 -C.sub.6 alkyl, NR.sup.7 CON(R.sup.7).sub.2, NR.sup.7 COW, SO.sub.2 W, or W;
R.sup.1 is C.sub.2 -C.sub.10 alkyl, C.sub.3 -C.sub.10 alkenyl, (CH.sub.2).sub.0-8 C.sub.3-6 cycloalkyl, or (CH.sub.2).sub.0-8 phenyl unsubstituted or substituted by one to three substituents selected from C.sub.1 -C.sub.6 alkyl, nitro, Cl, Br, F, I, hydroxy, C.sub.1 -C.sub.6 alkoxy, NR.sup.7 R.sup.7, CO.sub.2 R.sup.7, CN, CONR.sup.7 R.sup.7, W, NR.sup.7 COH, NR.sup.7 COC.sub.1 -C.sub.6 alkyl, NR.sup.7 COW, SC.sub.1 -C.sub.6 alkyl, SO.sub.2 C.sub.1 -C.sub.6 alkyl, or SO.sub.2 W;
R.sup.2 is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl, C.sub.1 -C.sub.6 alkyl, NR.sup.7 R.sup.7, CO.sub.2 R.sup.7, CONR.sup.7 R.sup.7, NO.sub.2, CN, phenyl, or W;
X is a single bond, S, or O;
R.sup.3 is H, C.sub.1-6 alkyl, C.sub.3-6 alkenyl, COC.sub.1-5 alkyl, or (CH.sub.2).sub.0-3 phenyl;
R.sup.4 is H, C.sub.1-6 alkyl, C.sub.3-6 alkenyl, or (CH.sub.2).sub.0-3 -phenyl;
R.sup.5 is CO.sub.2 R.sup.7, CONR.sup.7 R.sup.7, or tetrazol-5-yl;
each n independently is 0-4;
R.sup.6 is phenyl, naphthyl, 2-or 3-thienyl, 2-or 3-furyl, 2-, 3-, or 4-pyridyl, pyrimidyl, imidazolyl, thiazolyl, triazolyl, triazolyl, tetrazolyl, pyrazolyl, pyrrolyl, oxazolyl, or isoxazolyl, with each aryl or heteroaryl group being unsubstituted or substituted by C.sub.1-6 alkyl, C.sub.1-6 alkoxy, Cl, Br, F, I, NR.sup.7 R.sup.7, CO.sub.2 R.sup.7, CONR.sup.7 R.sup.7, SO.sub.3 H, SO.sub.2 NHR.sup.7, OH, NO.sub.2 W, SO.sub.2 C.sub.1 -C.sub.6 alkyl, SO.sub.2 W, SC.sub.1 -C.sub.6 alkyl, NR.sup.7 COH, NR.sup.7 COW, or NR.sup.7 COC.sub.1 -C.sub.6 alkyl;
W is C.sub.m F.sub.2m+1, wherein m is 1-4; and
each R.sup.7 independently is H or C.sub.1-6 alkyl;
or a pharmaceutically acceptable salt thereof.
Compounds of formula (IV) are prepared following the methods described in European Publication Number EP 0 427 463, published May 15, 1991.
Preferred compounds included within the scope of formula (II) are:
or a pharmaceutically acceptable salt thereof.
Substituted imidazoles of the formula (V) are disclosed in U.S. application Ser. No. 07/621,491, filed Nov. 30, 1990: ##STR5## in which:
R is adamantyl, or naphthyl, biphenyl, or phenyl, with each aryl group being unsubstituted or substituted by one to three substituents selected from halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, OH, CN, CO.sub.2 R.sup.3, tetrazol-5-yl, SO.sub.3 H, SO.sub.2 NHR.sup.3, NO.sub.2, W, SC.sub.1-6 alkyl, SO.sub.2 C.sub.1-6 alkyl, NHSO.sub.2 R.sup.3, PO(OR.sup.3).sub.2, CONR.sup.3 R.sup.3, NR.sup.3 R.sup.3, NR.sup.3 COH, NR.sup.3 COC.sub.1-6 alkyl, NR.sup.3 CON(R.sup.3).sub.2, NR.sup.3 COW, or SO.sub.2 W;
R.sup.1 is C.sub.2-10 alkyl, C.sub.3-10 alkenyl, (CH.sub.2).sub.0-8 C.sub.3-6 cycloalkyl, or (CH.sub.2).sub.0-8 phenyl unsubstituted or substituted by one to three substituents selected from C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halo, OH, NO.sub.2, NR.sup.3 R.sup.3, W, CO.sub.2 R.sup.3, CN, CONR.sup.3 R.sup.3, NR.sup.3 COH, tetrazol-5-yl, NR.sup.3 COC.sub.1-6 alkyl, NR.sup.3 COW, SC.sub.1-6 alkyl, SO.sub.2 W, or SO.sub.2 C.sub.1-6 alkyl;
X is a single bond, S, NR.sup.3, or O;
m is 0-4;
R.sup.2 is H, C.sub.1-6 alkyl, halo, W, CHO, CH.sub.2 OH, CO.sub.2 R.sup.3, CONR.sup.3 R.sup.3, NO.sub.2, CN, NR.sup.3 R.sup.3, or phenyl;
each R.sup.3 independently is H or C.sub.1-6 alkyl;
R.sup.4 is H, C.sub.1-8 alkyl, thienyl-Y-, furyl-Y-, pyrazolyl-Y-, imidazolyl-Y-, thiazolyl-Y-, pyridyl-Y-, tetrazolyl-Y-, pyrrolyl-Y-, triazolyl-Y-, oxazolyl-Y-, isoxazolyl-Y-, or phenyl-Y-, with each aryl or heteroaryl group being unsubstituted or substituted by C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halo, NR.sup.3 R.sup.3, CO.sub.2 R.sup.3, OH, NO.sub.2, SO.sub.2 NHR.sup.3, SO.sub.3 H, CONR.sup.3 R.sup.3, W, SO.sub.2 W, SC.sub.1-6 alkyl, SO.sub.2 C.sub.1-6 alkyl, NR.sup.3 COH, NR.sup.3 COW, or NR.sup.3 COC.sub.1-6 alkyl;
R.sup.5 is CO.sub.2 R.sup.3, CONR.sup.3 R.sup.3, or tetrazol-5-yl;
W is C.sub.q F.sub.2q+1, wherein q is 1-4;
Y is a single bond or C.sub.1-6 alkyl which is straight or branched; and
n is 0-5; or a pharmaceutically acceptable salt thereof.
Compounds of formula (V) are prepared following the methods described in European Publication Number EP 0 437 103, published Jul. 17, 1991.
Preferred compounds included within the scope of formula (V) are N-[{2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-yl}methylcarbonyl]-L- phenylalanine and N-[{2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-yl}methylcarbonyl]-L- (2-thienyl)alanine; or a pharmaceutically acceptable salt thereof.
Substituted imidazoles of the formula (VI) are disclosed in Patent Cooperation Treaty Application Number WO 91/04561, filed Jun. 26, 1991: ##STR6## in which:
R.sup.1 is adamantyl, or phenyl, biphenyl, or naphthyl, with each aryl group being unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I, C.sub.1 -C.sub.6 alkyl, nitro, CO.sub.2 R.sup.7, tetrazol-5-yl, C.sub.1 -C.sub.6 alkoxy, hydroxy, SC.sub.1 -C.sub.6 alkyl, SO.sub.2 NR.sup.7 R.sup.7, NHSO.sub.2 R.sup.7, SO.sub.3 H, CONR.sup.7 R.sup.7, CN, SO.sub.2 C.sub.1 -C.sub.6 alkyl, or C.sub.n F.sub.2n+1 ;
R.sup.2 is C.sub.2 -C.sub.10 alkyl unsubstituted or substituted by CO.sub.2 H, OH, or NR.sup.7 R.sup.7, C.sub.3 -C.sub.10 alkenyl, C.sub.3 -C.sub.10 alkynyl, C.sub.3 -C.sub.6 cycloalkyl, or (CH.sub.2).sub.0-8 phenyl unsubstituted or substituted by one to three substituents selected from C.sub.1 -C.sub.6 alkyl, nitro, Cl, Br, F, I, hydroxy, C.sub.1 -C.sub.6 alkoxy, NR.sup.7 R.sup.7, CO.sub.2 R.sup.7, CN, or CONR.sup.7 R.sup.7 ;
X is a single bond, S, or O;
R.sup.3 is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl, COOR.sup.7, CONR.sup.7 R.sup.7, NO.sub.2, or C.sub.n F.sub.2n+1 ;
each n is 1-3;
m is 0-4;
R.sup.4 is CO.sub.2 R.sup.7, CONR.sup.7 R.sup.7, or tetrazol-5-yl;
Y is a single bond or a carbonyl group;
R.sup.5 is hydrogen, C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.6 cycloalkyl, (CH.sub.2).sub.0-4 phenyl, or (CH.sub.2).sub.0-3 CH-diphenyl wherein each phenyl group independently is unsubstituted or substituted by one to three substituents selected from C.sub.1 -C.sub.6 alkyl, nitro, Cl, Br, F, I, hydroxy, C.sub.1 -C.sub.6 alkyl, NR.sup.7 R.sup.7, CO.sub.2 R.sup.7, or CONR.sup.7 R.sup.7 ;
R.sup.6 is hydrogen or C.sub.1-6 alkyl; and
each R.sup.7 independently is hydrogen, C.sub.1 -C.sub.4 alkyl, or (CH.sub.2).sub.0-4 phenyl; or a pharmaceutically acceptable salt thereof.
Preferred compounds included within the scope of formula (VI) are 3-[(2-chlorophenyl)methyl]-2-propylthio-N-butrylhistidine and 3-[(2-chlorophenyl)methyl]-2-n-butyl-N-butyrylhistidine; or a pharmaceutically acceptable salt thereof.
Compounds of formula (VI) are prepared as illustrated by Example 1.
Substituted imidazoles of the formula (VII) are disclosed in Patent Cooperation Treaty Number WO 91/05391, filed Jul. 30, 1991: ##STR7## in which:
R.sup.1 is adamanthylmethyl, or phenyl, biphenyl, or naphthyl, with each aryl group being unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I, C.sub.1-6 alkyl, nitro, CO.sub.2 R.sup.8, tetrazol-5-yl, C.sub.1-6 alkoxy, hydroxy, SC.sub.1-4 alkyl, SO.sub.2 NHR.sup.8, NHSO.sub.2 R.sup.8, SO.sub.3 H, CONR.sup.8 R.sup.8, CN, SO.sub.2 C.sub.1-4 alkyl, or C.sub.n F.sub.2n+1, wherein n is 1-3;
R.sup.2 is C.sub.2-10 alkyl, C.sub.3-10 alkenyl, C.sub.3-10 alkynyl, C.sub.3-6 cycloalkyl, or (CH.sub.2).sub.0-8 phenyl unsubstituted or substituted by one to three substituents selected from C.sub.1-6 alkyl, nitro, Cl, Br, F, I, hydroxy, C.sub.1-6 alkoxy, NR.sup.8 R.sup.8, CO.sub.2 R.sup.8, CN, or CONR.sup.8 R.sup.8 ;
X is a single bond, S, or O;
R.sup.3 is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl, CO.sub.2 R.sup.8, NO.sub.2, or C.sub.n F.sub.2n+1, wherein n is 1-3;
q is 0 to 4;
m is 0 to 2;
R.sup.4 is H or C.sub.1-6 alkyl;
z is 0 to 1;
R.sup.5 is C.sub.3-6 alkyl, C.sub.3-6 alkenyl, phenyl-Y-, 2-or 3-thienyl-Y-, 2-or 3-furyl-Y-, 2-, 3-, or 4-pyridyl-Y-, tetrazolyl-Y-, triazolyl-Y-, imidazolyl-Y-, pyrazolyl-Y-, thiazolyl-Y-, pyrrolyl-Y-, or oxazolyl-Y-, with each aryl ring being unsubstituted or substituted by C.sub.1-6 alkyl, Cl, Br, F, I, C.sub.1-6 alkoxy, NR.sup.8 R.sup.8, CO.sub.2 R.sup.8, or CONR.sup.8 R.sup.8 ;
Y is a single bond or C.sub.1-6 alkyl which is branched or unbranched;
R.sup.6 is CO.sub.2 R.sup.8, CONR.sup.8 R.sup.8, or tetrazol-5-yl;
R.sup.7 is H, CO.sub.2 R.sup.8, or C.sub.1-6 alkyl; and
each R.sup.8 independently is hydrogen, C.sub.1-6 alkyl, or (CH.sub.3).sub.0-4 phenyl;
or a pharmaceutically acceptable salt thereof.
A preferred compound included within the scope of formula (VII) is 3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzylpropanoi c acid or a pharmaceutically acceptable salt thereof.
Compounds of formula (VII) are prepared as illustrated by Example 2.
Substituted imidazoles of the formula (VIII) are disclosed in U.S. application Ser. No. 07/621,188, filed Nov. 30, 1990: ##STR8## in which:
R.sup.1 is adamantylmethyl, or phenyl, biphenyl, or naphthyl, with each aryl group being unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I, C.sub.1 -C.sub.6 alkyl, nitro, CO.sub.2 R.sup.5, C.sub.1 -C.sub.6 alkoxy, hydroxy, SC.sub.1 -C.sub.6 alkyl, SO.sub.2 C.sub.1 -C.sub.6 alkyl, tetrazol-5-yl, SO.sub.2 NHR.sup.5, NHSO.sub.2 R.sup.5, SO.sub.3 H, PO(OR.sup.5).sub.2, CONR.sup.5 R.sup.5, CN, NR.sup.5 R.sup.5, NR.sup.5 COH, NR.sup.5 COC.sub.1 -C.sub.6 alkyl, NR.sup.5 CON(R.sup.5).sub.2, NR.sup.5 COW, SO.sub.2 W, or W;
R.sup.2 is C.sub.2 -C.sub.10 alkyl, C.sub.3 -C.sub.10 alkenyl, (CH.sub.2).sub.0-8 -C.sub.3-6 cycloalkyl, or (CH.sub.2).sub.0-8 phenyl unsubstituted or substituted by one to three substituents selected from C.sub.1 -C.sub.6 alkyl, nitro, Cl, Br, F, I, hydroxy, C.sub.1 -C.sub.6 alkoxy, tetrazol-5-yl, NR.sup.5 R.sup.5, CO.sub.2 R.sup.5, CN, CONR.sup.5 R.sup.5, W, NR.sup.5 COH, NR.sup.5 COC.sub.1 -C.sub.6 -alkyl, NR.sup.5 COW, SO.sub.2 W, SO.sub.2 C.sub.1 -C.sub.6 alkyl, or SC.sub.1 -C.sub.6 alkyl;
X is a single bond, S, NR.sup.5, or O;
n is 0-4;
R.sup.3 is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl, C.sub.1 -C.sub.6 alkyl, NR.sup.5 R.sup.5, CO.sub.2 R.sup.5, CONR.sup.5 R.sup.5, NO.sub.2, CN, phenyl, or W;
R.sup.4 is CO.sub.2 R.sup.5, CONR.sup.5 R.sup.5, or tetrazol-5-yl;
Z is hydrogen, Cl, Br, F, I, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, hydroxy, CN, NO.sub.2, CO.sub.2 R.sup.5, COR.sup.5 R.sup.5, W, phenyl-Y-, naphthyl-Y-, thienyl-Y-, furyl-Y-, pyrazolyl-Y-, imidazolyl-Y-, thiazolyl-Y-, tetrazolyl-Y-, pyrrolyl-Y-, triazolyl-Y-, oxazolyl-Y-, or isoxazolyl-Y-, with each aryl or heteroaryl group being unsubstituted or substituted by C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, Cl, Br, F, I, CO.sub.2 R.sup.5, hydroxy, NO.sub.2, CN, CONR.sup.5 R.sup.5, or W;
Y is a single bond or C.sub.1 -C.sub.6 alkyl, which is straight or branched;
W is C.sub.m F.sub.2m+1, wherein m is 1-4,; and
each R.sup.5 independently is H or C.sub.1 -C.sub.6 alkyl;
or a pharmaceutically acceptable salt thereof.
A preferred compound included within the scope of formula (VIII) is 3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]benzoic acid or a pharmaceutically acceptable salt thereof.
Compounds of Example (VIII) are prepared as illustrated by Example 3.
Substituted benzimidazoles of the formula (IX) are disclosed in Patent Cooperation Treaty Publication Number WO 91/16313, published Oct. 31, 1991: ##STR9## in which:
R.sup.1 is --C(O)NH--CH(Y)--(CH.sub.2).sub.n -aryl, --C(O)NH--CH(Y)--(CH.sub.2).sub.n -heteroaryl, or phenyl unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, OH, CN, NO.sub.2, CO.sub.2 R.sup.4, tetrazol-5-yl, CONR.sup.4 R.sup.4, SO.sub.3 H, C.sub.m F.sub.2m+1, SC.sub.1-6 alkyl, or SO.sub.2 C.sub.1-6 alkyl;
R.sup.2 is hydrogen, C.sub.2-10 alkyl, C.sub.3-10 alkenyl, C.sub.3-6 -cycloalkyl, C.sub.m F.sub.2m+1, or (CH.sub.2).sub.0-8 phenyl unsubstituted or substituted by one to three substituents selected from C.sub.1-6 alkyl, C.sub.1-6 alkoxy, Cl, Br, F, I, OH, NO.sub.2, C.sub.m F.sub.2m+1, CO.sub.2 R.sup.4, or NR.sup.4 R.sup.4 ;
R.sup.3 is --(CH.sub.2).sub.n --Y, --CH.dbd.CY--(CH.sub.2).sub.n -aryl, --CH.dbd.CY--(CH.sub.2).sub.n -heteroaryl, --(CH.sub.2).sub.n --C(O)--NH--CH(Y)--(CH.sub.2).sub.n -aryl, --(CH).sub.2).sub.n --C(O)--NH--CH(Y)--(CH.sub.2).sub.n heteroaryl, --(CH.sub.2).sub.m --NH--CH(Y)--(CH.sub.2).sub.n -aryl or --(CH.sub.2).sub.m --NH--CH(Y)--(CH.sub.2).sub.n -heteroaryl, when R.sup.1 is an optionally substituted phenyl group; or H when R.sup.1 is --C(O)NH--CH(Y)--(CH.sub.2).sub.n -aryl or --C(O)NH--CH(Y)--(CH.sub.2).sub.n -heteroaryl;
Y is CO.sub.2 R.sup.4 or tetrazol-5-yl;
X is Cl, Br, F, I, C.sub.m F.sub.2m+1, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, OH, O-phenyl, CO.sub.2 R.sup.4, tetrazol-5-yl, CN, or (CH.sub.2).sub.0-4 phenyl unsubstituted or substituted by Cl, Br, F, I, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, OH, C.sub.m F.sub.2m+1, CN, CO.sub.2 R.sup.4, NO.sub.2, or NR.sup.4 R.sup.4 ;
aryl is phenyl, biphenyl, or naphthyl wherein each aryl group is unsubstituted or substituted by C.sub.1-6 alkyl, C.sub.1-6 alkoxy, Cl, Br, F, I, OH, NO.sub.2, CF.sub.3, CO.sub.2 R.sup.4, or NR.sup.4 R.sup.4 ;
heteroaryl is 2-or 3-thienyl, 2-, or 3-furanyl, 2-, 3-, or 4-pyridyl, pyrimidyl, imidazolyl, thiazolyl, triazolyl, or tetrazolyl wherein each heteroaryl group is unsubstituted or substituted by C.sub.1-6 alkyl, C.sub.1-6 alkoxy, Cl, Br, F, I, OH, NO.sub.2, CF.sub.3, CO.sub.2 R.sup.4, or NR.sup.4 R.sup.4 ;
each m independently is 1-3;
each n independently is 0-2; and
each R.sup.4 independently is H or C.sub.1-6 alkyl; or a pharmaceutically acceptable salt thereof.
Preferred compounds included within the scope of formula (IX) are:
or a pharmaceutically acceptable salt thereof.
Compounds of formula (IX) are prepared following the methods described in Patent Cooperation Treaty Publication Number WO 91/16313, published Oct. 31, 1991. Formula (IX) compounds are prepared as illustrated by Example 4.
The above descriptions on pages 3-18 of classes of AII receptor antagonists for use in the present invention were taken from the noted patent applications and publications. Reference should be made to such patent applications and publications for their full disclosure, the entire disclosure of each of which is incorporated herein by reference.
Also included within the scope of this invention are pharmaceutical compositions comprising a pharmaceutically acceptable carrier in association with a compound of formula (I)-(IX) and a second therapeutic agent, such as a diuretic, a calcium channel blocker, a .beta.-adrenoceptor blocker, a renin inhibitor, or an angiotensin converting enzyme inhibitor.
This invention also relates to a method of treating hypertension by administering a compound of formula (I)-(IX) stepwise or in physical combination with a diuretic, a calcium channel blocker, a .beta.-adrenoceptor blocker, a renin inhibitor, or an angiotensin converting enzyme inhibitor.
Most advantageously the compositions of this invention in dosage unit form are comprised of (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl-1H-imidazol-5-yl]-2-(2-thienyl )methyl-2-propenoic acid, or a pharmaceutically acceptable salt thereof, and a diuretic, a calcium channel blocker, a .beta.-adrenoceptor blocker, a renin inhibitor, or an angiotensin converting enzyme inhibitor. Either can alternatively be used in the form of a non toxic salt.
Pharmaceutically acceptable acid addition salts of compounds of Formula (I)-(IX) are formed with appropriate organic or inorganic acids by methods known in the art. For example, the base is reacted with a suitable inorganic or organic acid in an aqueous miscible solvent such as ethanol with isolation of the salt by removing the solvent or in an aqueous immiscible solvent when the acid is soluble therein, such as ethyl ether or chloroform, with the desired salt separating directly or isolated by removing the solvent. Representative examples of suitable acids are maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, hydrochloric, hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric and nitric acids.
Pharmaceutically acceptable base addition salts of compounds of Formula (I)-(IX) wherein a carboxy group is present are prepared by known methods from organic and inorganic bases, including nontoxic alkali metal and alkaline earth bases, for example, calcium, lithium, sodium, and potassium hydroxide; ammonium hydroxide, and nontoxic organic bases, such as triethylamine, butylamine, piperazine, meglumine, choline, diethanolamine, and tromethamine.
Angiotensin II antagonist activity of the compounds of Formula (I)-(IX) is assessed by in vitro and in vivo methods. In vitro antagonist activity is determined by the ability of the compounds to compete with .sup.125 I-angiotensin II for binding to vascular angiotensin II receptors and by their ability to antagonize the contractile response to angiotensin II in the isolated rabbit aorta. In vivo activity is evaluated by the efficacy of the compounds to inhibit the pressor response to exogenous angiotensin II in conscious rats and to lower blood pressure in a rat model of renin dependent hypertension.
Binding
The radioligand binding assay is a modification of a method previously described in detail (Gunther et al., Circ. Res. 47:278, 1980). A particular fraction from rat mesenteric arteries is incubated in Tris buffer with 80 pM of .sup.125 I-angiotensin II with or without angiotensin II antagonists for 1 hour at 25.degree. C. The incubation is terminated by rapid filtration and receptor bound .sup.125 I-angiotensin II trapped on the filter is quantitated with a gamma counter. The potency of angiotensin II antagonists is expressed as the IC.sub.50 which is the concentration of antagonist needed to displace 50% of the total specifically bound angiotensin II. The IC.sub.50 of (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl}-2-(2-thieny l)methyl-2-propenoic acid is about 1.0 nM.
Aorta
The ability of the compounds to antagonize angiotensin II induced vasoconstriction is examined in the rabbit aorta. Ring segments are cut from the rabbit thoracic aorta and suspended in organ baths containing physiological salt solution. The ring segments are mounted over metal supports and attached to force displacement transducers which are connected to a recorder. Cumulative concentration response curves to angiotensin II are performed in the absence of antagonist or following a 30-minute incubation with antagonist. Antagonist disassociation constants (K.sub.B) are calculated by the dose ratio method using the mean effective concentrations. The K.sub.B of (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl}-2-(2-thieny l)methyl-2-propenoic acid is about 0.20 nM.
Inhibition of pressor response to angiotensin II in conscious rats
Rats are prepared with indwelling femoral arterial and venous catheters and a stomach tube (Gellai et al., Kidney Int. 15:419, 1979). Two to three days following surgery the rats are placed in a restrainer and blood pressure is continuously monitored from the arterial catheter with a pressure transducer and recorded on a polygraph. The change in mean arterial pressure in response to intravenous injections of 250 mg/kg angiotensin II is compared at various time points prior to and following the administration of the compounds intravenously or orally at doses of 0.1 to 300 mg/kg. The dose of compound needed to produce 50% inhibition of the control response to angiotensin II (IC.sub.50) is used to estimate the potency of the compounds. The IC.sub.50 of (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thieny l)methyl-2-propenoic acid is about 0.1 mg/kg i.v. and about 5.5 mg/kg orally.
Antihypertensive activity
The antihypertensive activity of the compounds is measured by their ability to reduce mean arterial pressure in conscious rats made renin-dependent hypertensive by ligation of the left renal artery (Cangiano et al., J. Pharmacol. Exp. Ther. 208:310, 1979). Renal artery ligated rats are prepared with indwelling catheters as described above. Seven to eight days following renal artery ligation, the time at which plasma renin levels are highest, the conscious rats are placed in restrainers and mean arterial pressure is continuously recorded prior to and following the administration of the compounds intravenously or orally. The dose of compound needed to reduce mean arterial pressure by 30 mm Hg (IC.sub.30) is used as an estimate of potency. The IC.sub.30 of (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thieny l)methyl-2-propenoic acid is about 10.0 mg/kg orally.
The antihypertensive activity of the claimed pharmaceutical composition is determined using the spontaneously hypertensive rat model. The details of this in vivo test are found in Roesler, J. M., et al., J. Pharmacol. Exp. Ther., 236:1-7 (1986).